The invention relates to a novel oral pharmaceutical form containing microgranules, this form being with the sustained release of at least one active ingredient and with release kinetics enabling notably a single daily dose taken by the patient while preventing this release from accelerating due to the simultaneous consumption of alcohol.
Many sustained-release oral pharmaceutical forms exist on the market. The release of the active ingredient must be controlled according to the therapeutic objective and the pharmacological properties of the active ingredient. Certain active ingredients prove to be highly toxic, even deadly, if the ingested dose exceeds a certain threshold.
It is thus imperative that their “delay” properties are strictly controlled in order to ensure that the rapid release of the active ingredient (“dose dumping”) cannot occur, notably when alcohol is consumed at the same time. The consumption of alcohol at the same time as a dose of a drug can indeed alter the pharmaceutical form, which then very rapidly releases all of the active ingredient contained therein. Furthermore, to improve patient comfort, it is desirable to provide a drug that has a pharmacological effect over a long period of time after administration.
For example, this is particularly true for people suffering from severe pain and for whom the pharmacological response must be maintained over a long period with a constant therapeutic level over time.
In order to evaluate the alcohol resistance of pharmaceutical compositions, the United States Food and Drug Administration (FDA) suggests performing in vitro dissolution tests to compare the kinetics obtained in 0.1 N HCI medium (representative of gastric pH) with the kinetics obtained in the same medium substituted with 5%, 20% and 40% (v/v) ethanol. According to Walden et al. (The Effect of Ethanol on the Release of Opioids 30 from Oral Prolonged-Release Preparations, Drug Development and Industrial Pharmacy, 33:10, 1101-1111, 2007), the fact of exposing in vitro a pharmaceutical form over a period of 2 h is regarded as representative of the exposure time of these pharmaceutical forms in vivo.
Patent EP1189602, known from the state of the art, describes sustained release morphine sulfate microgranules. This document proposes microgranules comprised of a neutral carrier coated with an active layer and a sustained release layer containing a copolymer of methacrylic acid and methyl methacrylate ester as well as hydrophobic silica. However, this form of microgranule has the disadvantage of very quickly releasing the active ingredient in the presence of alcohol, which can be harmful or even lethal to 10 the patient.
Patent application WO2010037854, also known from the state of the art, proposes to use a carrier of neutrals that are insoluble or are made insoluble in water or alcohol to avoid an immediate release of the active ingredient induced by the consumption of alcohol. However, this carrier is limited in terms of its resistance to alcohol since the maximum percentage of ethanol in the dissolution medium is 30% and thus this carrier would not resist large volumes of strong alcohols such as whiskey or vodka. Moreover, this patent application does not make it possible to obtain dissolution kinetics compatible with a single daily administration.
Applications WO2009/036812 and WO2010/034342 relate to pH-dependent controlled-release pharmaceutical compositions comprising opioids whose dissolution kinetics are not appreciably affected by the presence of ethanol. More particularly, these pharmaceutical compositions are essentially comprised of a core containing the active substance onto which is coated a layer of a mixture of polymer and a mixture of inert lubricant.
However, the description forces the use of pH-dependent polymers which can induce changes in behavior in man depending on the individual and the conditions under which the drug was taken (notably with or without food).
An essential objective of the present invention is thus to propose an oral pharmaceutical form containing microgranules with sustained release of at least one active ingredient, making it possible to avoid or limit an immediate release of the active ingredient induced by the consumption of alcohol during the administration of this pharmaceutical form. Furthermore, this pharmaceutical form must be easy to produce industrially and at a lower cost.
Definitions in the context of the present description of the invention:
Neutral Carrier
The term “neutral carrier” or “neutral core” or more simply “neutral” means spherical or quasi-spherical inert carriers of a size between 50 μm and 3 mm, preferentially between 100 μm and 1000 μm, such as those generally used in the pharmaceutical industry as a carrier base for active ingredients for the production of microgranules, for example.
Microgranules
The microgranules of the present invention relate to spherical galenic units, comprised in their center of a neutral carrier, covered with at least one layer containing the active ingredient which itself is covered with at least one polymer layer.
Pharmaceutical Form
The term “oral pharmaceutical form” refers to any oral pharmaceutical form that can be prepared from microgranules comprising the active ingredient, notably a suspension, syrup, tablet, gelatin capsule or sachet.
Sustained Release
In the present application, the term “sustained release” will be used to indicate a release profile of the active ingredient that is modified compared to that which the active ingredient alone would have had in an immediate release system as defined by the European Pharmacopoeia (quantity of active ingredient released in 45 minutes at least equal to 75%, Ph. Eur., 6th edition 2.9.3.)
Alcohol
The term “alcohol” refers to ethanol and the terms “alcohol solution” and “alcohol medium” refer to an aqueous ethanol solution.
The goal of the present invention is to provide a novel oral pharmaceutical composition resistant to the immediate release of the dose of active ingredient due to alcohol and notably enabling a single dose daily.
Preferentially, the expression “resistance to the immediate release of the dose of active ingredient due to alcohol” or “resistance to alcohol” means that the percentage of active ingredient released after 2 hours in a 0.1 N HCI acid-alcohol medium containing alcohol and preferably a quantity of ethanol between 4% and 40% (for example 10%, 20%, 30% or 40%) is not greater by more than 15 percentage points (15% in absolute value) than that released in a medium of 0.1 N HCI.